ABSTRACT ? Overall (Sallie Permar, PI; Duke University) Almost 2 million children are infected with HIV worldwide, and every year more than 150,000 new pediatric HIV infections occur. Postnatal breast milk transmission accounts for at least half of these new infections. Current standard of care commits HIV-infected children to lifelong, daily antiretroviral treatment (ART). A cure is needed to provide HIV-infected children a life without the medical complications, pharmacological burden, and social stigma associated with HIV-1 infection. While early initiation of ART leads to prolonged virus suppression, the virus rebounds after treatment cessation due to the persistence of virus reservoirs. However, there is hope that strategies to reduce or eliminate virus reservoirs could lead to long-term remission, as demonstrated by the over two-year ART-free remission that was demonstrated in the case known as `the Mississippi baby'. Using a highly relevant animal model, the overall goal of our Program is to define the origin, kinetics, and predictors of viral rebound in postnatally-infected infants, as well as assess the potential impact of immune-based interventions to eradicate pediatric HIV reservoirs. Our central hypothesis is that the origin and kinetics of viral rebound in postnatally infected infants can be predicted through biomarker measurement (Project 1) and can be extended through the enhancement of antiviral humoral and T cell immunity (Project 2). Specifically, we will use a highly translational animal model of pediatric HIV infection and long-term ART treatment to accomplish the following Specific Aims: 1) Define the origin, kinetics, and predictors of viral rebound following long term ART treatment in our animal model of postnatal infection; 2) Define the impact of passive immunization with broadly-neutralizing antibodies and T cell-based vaccine on viral rebound in our animal model of postnatal infection; and 3) Develop a mathematical model that will define the primary contributing factors and the potential efficacy of immune-based interventions on viral rebound following postnatal infection. Successfully completed, this Program will use our highly translational animal model to uniquely define the tissue origin, kinetics, and viral sequences of viral rebound, guiding development and evaluation of pediatric-specific HIV cure strategies; define biomarkers that can be used to clinically predict viral rebound; and evaluate the impact of immune-based interventions on viral rebound. Together, these results will help guide the design of passive and active vaccine strategies to achieve long-term remission or cure in human infants.